Clinicopathological Features of and Risk Factors for Multiple Primary Melanomas FREE

The phenomenon of multiple primary tumors occurring within a single organ or organ system has been well documented.¹ Whether this is a function of an increased genetic susceptibility of the individual patient (eg, in familial polyposis and colorectal cancer), consistent exposure to a common exogenous promoter of malignancy (eg, cigarette smoke and lung cancer), or a combination of these 2 factors varies from one patient to the next and from one organ system to the next. Malignant melanoma epitomizes much of what is known about multiple primary tumors.

In 2005, there will be an estimated 62 000 new cases of invasive melanoma and an estimated 7600 deaths due to melanoma in the United States.² Melanoma is the fifth leading cancer in men and the sixth leading cancer in women in the United States.² The incidence of melanoma continues to rise at about 3.0% per year in the United States, with an estimated lifetime risk for an individual of 1.4%.^1- 2 This increasing incidence puts a larger portion of the population at risk not only for 1 primary melanoma but also for subsequent primary melanomas.³ Among patients with a history of a primary melanoma, retrospective reviews report the incidence of a second primary tumor to range from 0.2% to 8.6%^3- 13 (Table 1). The Surveillance, Epidemiology, and End Results (SEER) database from 1996-2001 includes 22 688 patients with a single melanoma and 465 patients with more than 1 melanoma, for an incidence of 2.0%.

Since Pack et al⁵ first described the phenomenon of multiple primary melanomas (MPM) in 1952, patients with this disease have not been well characterized. The clinical manifestations of MPM are broad. While 63% to 88% of patients with MPM are reported to have 2 primary tumors,^3,5- 10 a patient with as many as 48 separate primary melanomas has been reported.⁶

Several risk factors associated with the development of MPM have been identified. These include a positive family history of MPM and a personal history of dysplastic nevi (DN), atypical moles that are risk markers but nonobligate precursors of melanoma.^12- 16 Among patients with MPM, 18% to 38% are reported to have a positive family history of melanoma^4,11 and 38% to 46% are reported to have a history of dysplastic nevi.^3- 4 However, few longitudinal cohort-defined databases have prospectively recorded known risk factors for all patients with melanoma to assess the impact of these risk factors on the development of MPM.

The main difficulty in estimating the incidence of MPM is that it requires careful follow-up of large populations of melanoma patients over long periods of time, with specific effort to capture antecedent, synchronous, or subsequent melanomas.

This is the first study, to our knowledge, to use a prospective, multidisciplinary, single-institution database to identify the characteristics of patients at risk of developing MPM. This study defines the estimated incidence of MPM among a cohort of consecutive patients treated for melanoma at a tertiary cancer referral center. Specific patient characteristics, prospectively collected, included family history and presence of DN. Tumor characteristics were evaluated with specific attention to the number of melanomas diagnosed, the time course over which melanomas were diagnosed, the timing of the thickest melanomas (initial vs subsequent), the location of subsequent melanomas, and the prevalence of melanoma in situ. In addition, these characteristics among MPM patients were compared with those of patients with single primary melanoma (SPM) in the same prospective database.

A prospective, computerized, multidisciplinary melanoma database at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, was used to identify a constructed cohort of 4484 patients diagnosed as having an initial primary melanoma between January 1, 1996, and December 31, 2002, after approval from the institution’s internal review board. Patients diagnosed as having in situ and/or invasive melanomas, who had given either written or oral consent to be entered into the database, were included in the study cohort. Patients with MPM were defined as those with 2 or more primary melanomas based on review of pathology reports from MSKCC and outside institutions. All primary tumors had clear epidermal involvement documented on pathology reports. Recurrences, in transit, and distant metastases were excluded. Patient characteristics recorded included age at diagnosis of first melanoma, sex, family history, and presence of DN. Positive family history was defined as the history of a first-degree relative diagnosed as having melanoma. The majority of DN were diagnosed clinically by an MSKCC dermatologist. If a patient had a history of multiple nevi excisions with a histological diagnosis of DN, the patient was classified as having DN even if there were no remaining DN on clinical examination. Dysplastic nevi were defined pathologically as the presence of a single clinically unequivocal (>5 mm with color variegation and fuzzy border) or histologically proven dysplastic nevus.¹⁴

For each primary melanoma diagnosed, the date of diagnosis, location, thickness, Clark level, and ulceration status were recorded. Melanomas were classified as being located in the head/neck, trunk (including chest, back, abdomen, and inguinal regions), extremity (including shoulders, arms, and legs), or mucosa (including anorectal and vulvar). Ocular melanomas were recorded as a separate site. Synchronous melanomas were defined as those diagnosed within 30 days of each other.

The Fisher exact test was used to compare the single vs multiple primary groups with regard to sex, family history of melanoma, and presence of DN. For the continuous variables, age and thickness, the single and multiple primary groups were compared using a 2-sided t test. The incidence of second primary melanoma over time was calculated using a competing risk analysis accounting for death as a competing risk.¹⁷ Time to second melanoma or death was calculated from the date of first melanoma to the date of second melanoma, death, or last follow-up. The age-adjusted standardized incidence ratio (SIR) for second primary melanoma was estimated as the number of patients diagnosed as having MPM (observed) divided by the number of diagnoses expected based on person-years of follow-up and incidence rates for each age group from SEER cancer registries. Using SEERStat, version 5.3.1 (National Cancer Institute, Bethesda, Md), we estimated the SIR for second primary melanoma in the SEER population. P<.05 was considered statistically significant.

Three hundred eighty-five of 4484 patients were identified as having MPM, for an overall incidence of 8.6%. The 4099 SPM patients were followed up for a median of 2.2 years (range, 0-8.8 years). An actuarial curve was constructed for all 4484 patients with the event of interest being the development of a second primary melanoma. The incidence curve of death without a second primary tumor was also included (Figure, A). The incidence of death without a second primary tumor is higher than the incidence of developing a second primary tumor, which is one of the reasons more patients do not develop a second primary melanoma. For the entire cohort of patients, the cumulative estimated 5-year risk of a second primary tumor was 11.4% (95% confidence interval, 10.2%-12.6%), with more than half (5.5%) of that risk occurring within the first year. Once a patient had developed a second primary melanoma, the cumulative estimated 5-year incidence of a third primary melanoma from the date of the second one was even higher at 30.9%, with half of that risk (15.6%) occurring within the first year.

Sex and Age at Diagnosis. The majority of patients both with MPM and with SPM were male (Table 2). The mean age at initial diagnosis for all patients was 55 years (median, 56 years; range, 1-99 years), with a significant difference (P = .003) between those with SPM (mean, 55 years; median, 56 years; range, 1-99 years) and those with MPM (mean, 58 years; median, 60 years; range, 11-90 years). In both the MPM and SPM cohorts, male patients were significantly older than female patients at the time of diagnosis of their first melanoma. Despite developing melanoma at an earlier age, women had a longer time interval for development of a second primary tumor than men. This could be because younger patients (<60 years) have a lower incidence of second primary melanoma than older patients (P<.001). The estimated 5-year incidence of second primary melanoma was 9.8% for young patients (<60 years) vs 13.3% for older patients. The mean age at diagnosis of the first primary tumor for men with MPM was 61 years (range, 11-89 years) compared with 52 years for women with MPM (range, 20-90 years) (P<.001). These age characteristics are similar to those of patients in our database with SPM, where the mean age at diagnosis for men was 57 years (range, 7-97 years) compared with 53 years (range, 1-99 years) for women (P<.001).

Family History and DN. Patients with MPM were significantly more likely to have a positive family history of melanoma, a history of DN, or both than patients with SPM (Table 2). A positive family history, the presence or absence of melanoma in a first-degree relative, was determined in 4459 patients. The overall prevalence of a positive family history was 578/4459 (13%). Of the 385 MPM patients, 81 (21%) had a positive family history compared with 497 (12%) of 4075 SPM patients. The incidence of second primary melanoma was significantly higher (P<.001) among those with a positive family history, with rates at 1 and 5 years of 8.3% and 19.1% compared with 5.1% and 10.3% for those with a negative family history (Figure, B and Table 3).

Presence or history of DN was determined in 3380 patients, with an overall prevalence of DN of 788/3380 (23%). Of 375 MPM patients, 145 (39%) had a history of DN compared with 643 (18%) of 3505 SPM patients. The incidence of MPM was significantly higher among those with DN, with rates at 1 and 5 years of 11.1% and 23.6% compared with 4.8% and 9.7% for patients without DN (P<.001) (Figure, C and Table 3).

Patients with both a positive family history and DN did not have a significantly higher incidence of a second primary tumor compared with patients who had either a positive family history or DN, most likely because of the strong effect of DN. The lowest incidence of MPM was seen in patients with neither a positive family history nor DN, with 1- and 5-year incidences of 4.3% and 9.0%, respectively (Figure, D and Table 3).

Number of Primary Melanomas. A total of 885 primary melanomas were identified in 385 MPM patients (mean, 2.3 melanomas per patient). Of these patients, 78% had 2 primary tumors, 15% had 3 primary tumors, 5% had 4, and 2% had 5 or more. The number of primary tumors ranged from 2 to 7.

Location of MPM. Location of the melanomas for the SPM and MPM patients is presented in Table 4 and Table 5. The distribution of initial melanoma sites was similar when comparing MPM and SPM. Additionally, for MPM patients the distribution of sites of subsequent melanomas was similar to that of initial melanomas. The initial and second melanomas occurred on the same body site in 49% of patients (190/385). Of the 61 patients who had an initial melanoma in the head and neck region, 20 (33%) had a second primary tumor at this anatomical site. Of the 169 patients who had an initial primary tumor on the trunk, 81 (48%) also had a second melanoma on the trunk. The highest body site concordance was seen among the 148 patients who had an initial primary melanoma on the extremities; 89 (60%) of these patients had a second primary melanoma on the extremities.

Timing of MPM. Synchronous melanomas occurred in 139 MPM patients (36%) at some point in their disease course. Most of these patients initially presented with 2 (n = 105) or 3 (n = 16) primary melanomas, and the rest (n = 18) developed synchronous primary melanomas subsequent to the first melanoma diagnosis. Twenty-two of the 121 patients who presented with synchronous melanomas had at least 1 subsequent primary melanoma.

Thickness of MPM. Of the 385 MPM patients, adequate information on the thickness of all melanomas was known for 352 patients. Of these 352 patients, 60 had melanomas of equal thickness (52 with melanoma in situ and 8 with invasive melanoma) and 93 patients had synchronous melanomas of unequal thickness. For the remaining 199 patients with nonsynchronous MPM of unequal thickness, the thickest melanoma was the initial melanoma in 147 patients (74%) and was the subsequent melanoma in 52 patients (26%). Excluding the 139 patients with synchronous melanomas, the mean and median thickness of the initial melanoma were 1.2 mm and 0.5 mm, compared with a mean and median thickness for subsequent melanomas of 0.4 mm and 0 mm, respectively (range, 0-8 mm; P<.001).

The initial melanoma was also significantly thinner in MPM patients compared with SPM patients. The mean and median thicknesses of the initial primary for MPM patients (n = 224) were 1.2 mm and 0.5 mm (range, 0-17 mm) compared with mean and median thicknesses of 2.0 mm and 0.9 mm (range, 0-52 mm) for primary tumors in SPM patients (n = 3312) (P<.001).

Melanoma In Situ. Among MPM patients, 61% (234/385) had at least 1 melanoma in situ (MIS) at some point in their clinical course. Of these 234 patients, 52 had exclusively MIS, 175 had MIS and at least 1 invasive melanoma of known thickness, and 7 patients had MIS and a melanoma of unknown thickness. Melanoma in situ was more prevalent among subsequent primary melanomas. Among patients with known thickness, 21% of 385 initial melanomas were MIS, 50% of 385 second melanomas were MIS, 55% of 83 third melanomas were MIS, and 70% of 23 fourth melanomas were MIS. In contrast, 17% of 3312 SPM patients with known thickness had MIS.

Multiple primary melanomas were identified in 8.6% of a constructed cohort of patients from our prospective, multidisciplinary, single-institution database, which is consistent with other large retrospective studies, in which the incidence ranged from 1.3% to 8.0%^5- 6 (Table 1). The overall number of melanomas and number of synchronous melanomas diagnosed are consistent with other large studies. Similar to the 48% reported in the study by Giles et al,¹¹ 49% of our cohort had their second primary tumor on the same body site as their first primary tumor. However, Giles et al reported the highest site concordance, 58%, in the head and neck region, whereas the highest site concordance in our study was 60% in the extremities.

Analysis of the time interval between the first and second melanomas demonstrated that 59% of MPM patients have their second primary within the first year, slightly higher than reports by Slingluff et al⁶ and Kang et al,⁸ who documented 51% of second primary tumors within the first year.

Based on absolute thickness, the thickest melanoma was the first melanoma for the majority of MPM patients. In the MPM cohort, the percentage of melanoma in situ also increased with each subsequent primary melanoma, further confirming the trend toward thinner subsequent melanomas. Brobeil et al⁷ made a similar observation. This trend toward thinner melanomas is likely due to improved surveillance and early detection, but less aggressive disease biology in the MPM patients may also play a role, since the initial melanomas in MPM patients were significantly thinner than the melanomas in the SPM cohort. This may also explain the difference in disease-specific death between the MPM and SPM cohorts. Of the MPM patients, 5.6% (29/385) died from melanoma compared with 15.8% of SPM patients (649/4099).

Considerable debate surrounds the clinical significance of the diagnosis of MIS. Blackwood et al,⁴ Slingluff et al,⁶ Kang et al,⁸ and Johnson et al¹⁰ all included MIS in their analyses. However, the 37 700 new annual cases of MIS are not included in the yearly incidence of melanoma cases reported.² To address the concern surrounding the true biology of MIS and its classification as a true melanoma or a precursor lesion, we performed another analysis excluding patients with MIS. Interestingly, when patients who had only MIS or only 1 invasive melanoma and MIS were excluded from the analysis, the incidence of invasive MPM dropped to 5.7% (165/2905); however, the demographics of the subset analyses remains constant. Of the 165 patients with at least 2 invasive melanomas, 68% were male, 20% had a positive family history, and 38% had DN. Although the subset of patients with 2 invasive melanomas was smaller, the trends remained consistent with the entire cohort of MPM patients.

Because the entity of DN is relatively recent, many of the older retrospective analyses were not able to determine its prevalence. In our study, MPM patients with DN presented at a significantly younger age than MPM patients without DN. Despite presenting at a younger age, they did not appear to have a greater number of primary tumors per patient, with 2.4 melanomas per patient. The thickest melanomas in patients with SPM and MPM and with DN were significantly thinner than in patients without DN. This may be the result of better surveillance or less aggressive disease biology, despite the predisposition to multiple primary melanomas.

The estimated cumulative 5-year risk of a second primary melanoma in our 4484 patients is 11.4%, which is somewhat higher than reported in the other studies (Table 1). This difference may be due to the prospective collection of data or to the referral pattern of a tertiary cancer center such as MSKCC. To assess the potential impact of lead time bias, we analyzed the subset of patients whose diagnoses were made at MSKCC. Since the resulting prevalence and incidence results were similar to the entire cohort, we believed that the effect of selection bias was minimal.

Of the 11.4%, roughly half of the risk was accrued within the first year, in large part because of the frequency of MPM patients presenting with more than 1 primary melanoma. After the first year, the remaining 6.0% risk accrued over years 2 through 5 at a rate somewhat higher than the yearly risk calculated by Slingluff et al⁶ of 0.38% per year. One melanoma put patients at risk of a second primary melanoma, and a second primary melanoma put patients at even higher risk of a third primary melanoma. After a second primary melanoma, the incidence of a third primary melanoma almost tripled. The 1- and 5-year incidences of a third primary melanoma from the date of the second primary melanoma were 15.6% and 30.9%, respectively.

When comparing our cohort with the SEER database, our SIR for a second primary tumor was significantly higher. The SEER database for 1996-2001 included 22 688 patients with a primary melanoma, of whom 465 had second primary tumors over 55 932 person-years at risk, for an SIR of 18.58. For our cohort of 4484 patients with 385 MPM over 10 957 person-years at risk, the SIR was 122. If we exclude patients with synchronous melanomas from the SEER cohort as well as from our own cohort, the number of patients with MPM drops to 310 with an SIR of 12.8 in the SEER database and 246 with an SIR of 78.7 in the MSKCC data set. The significant difference in the incidence and SIR between the SEER data and our cohort can be partially attributed to the difference between a population-based cohort compared with an institutional cohort. The SEER database comprises 10 statewide registries, whereas the MSKCC cohort includes patients from a single tertiary cancer center. Also contributing to the difference in SIR between the 2 data sets is the prospective nature of the MSKCC database and the arduous task of reporting MPM.

As expected, the risk of subsequent primary melanoma is even higher for patients with a positive family history, DN, or both, at 19.0%, 23.6%, and 29.9% at 5 years from initial diagnosis of melanoma, respectively. Interestingly, the risk for patients with no family history or DN is still roughly 1.2% per year after the first year. However, unlike in the other patient subsets, the risk begins to level off for these patients, with a risk of 8.2% at 4 years and 9% at 5 years. This is in contrast with patients with a positive family history and DN, whose risk increases 1.5% and 1.1% in years 4 and 5, respectively.

The substantially higher rate of positive family history and DN in MPM patients offers a unique opportunity to further characterize melanoma risk at a genetic level. Mutations in the tumor suppressor gene CDKN2A and the proto-oncogene CDK4 have been identified in patients with a positive family history and MPM; however, the clinical relevance and impact of these mutations is not clear.^15- 16 The frequency of a CDKN2A mutation is less than 2% in all melanoma patients.¹⁷ This rises to 8% to 12% in patients with sporadic MPM and to an astonishing 47% in patients with MPM and a positive family history.^18- 19 By further studying this high-risk cohort with an increased frequency of mutations, better understanding of the genotype, phenotype, penetrance, and clinical variability can be gained.

Dysplastic nevi are estimated to be present in 5% to 10% of the general population.^20- 21 In our cohort of SPM patients, the rate was 18%, which may be attributed to MSKCC’s being a tertiary care center that attracts high-risk patients. Similar to other reported series, the rate of DN in our cohort of MPM patients was 39%. Patients with DN are predisposed not only to SPM but also to MPM. Further genetic characterization of these patients could help to identify some of the underlying molecular mechanisms specific to melanoma susceptibility.

All melanoma patients are counseled to undergo not only lifelong annual dermatologic follow-up for the detection of additional primary melanomas but also to perform self-examinations and behavior modifications. In the higher-risk cohorts with MPM, positive family history, or DN it may be prudent for patients to be seen more often than annually. For patients with multiple atypical nevi, a photographically assisted follow-up may also be indicated.

Patients diagnosed as having melanoma are at increased risk of developing additional primary melanomas. In our patient cohort, the incidence of MPM was 8.6%, with a 5-year estimated cumulative risk of a second primary melanoma of 11.4%. Patients with a positive family history or a history of DN are at significantly greater risk of developing MPM and should be enrolled in more intensive dermatologic surveillance programs. This high-risk subset of patients should also be further characterized genetically to further elucidate the biology and etiology of melanoma.